Influenza A viruses belong to the orthomyxoviridae family with a negative-sense, segmented RNA genome, which can cause seasonal or pandemic flu with high morbidity and significant mortality. Vaccination is the most prevalent prophylactic means for controlling influenza infections. However, an effective vaccine usually takes at least 6 months to develop for the circulating strains. Furthermore, vaccination has limited effectiveness in treatment of immunocompromised patients, and its effectiveness is also limited during a pandemic. The current therapeutic options for flu infections are all based on the NA inhibitors (NAIs), while the influenza M2 ion channel blockers (amantadine and rimantadine) are not recommended anymore since all the circulating influenza strains are resistant to them. However, the rapid emergence of the NAI-resistant strains of influenza A viruses strongly suggest that NAIs alone may not be sufficient as an effective means of the anti-flu therapies, and thus new treatment options targeting the other viral/host factors are urgently needed. This application defines a plan to develop potent, small molecule inhibitors, which block entry of influenza A viruses. We have identified compounds that inhibit entry of infectious influenza A viruses (IC50 values ?1 M). These hit compounds exhibit selectivity for H1N1 and H5N1 entry. The overall objective of this Phase I application is to develop these inhibitors as potential anti-flu therapeutics. This application will focus on the following three specific aims: (1) Synthesize structurally diverse analogs of the anti-flu CBS1116 hit series based on structure-activity relationships (SARs) to improve potency and selectivity. (2) Validate the lead inhibitor candidates in the infectious assay and investigate the mechanism of action (MOA) of the inhibitors. (3) Select flu inhibitors with in vitro ADME properties suitable for i.v. and oral dosing.